Certain 16, 17-oxido-steroids of the c21 series



United States PatentO CERTAIN 16,17-XIDO-STEROIDS OF THE C SERIES 0Percy L. Julian, Oak Park, Edwin W; Meyer, Chicago,

and Isabelle Waller, Northbrook, Ill., and William J. Karpel, deceased,late of Chicago, Ill., by Ruth Betty Karpel, legal representative,Chicago, 'Ill., assignors to The Glidden Company, Cleveland, Ohio, acorporation of Ohio No Drawing. Original application February 8,1950,Serial No. 143,146. Divided and fliis application Februmy 21, 1957,Serial No. 641,767

6 Claims. (Cl. 2 60-23955) The present invention relates tointermediates useful for preparing 2l-hydroxy-ZO-keto-l7-oxygenatedpregnenes and pregnanes.

Practically all of the known methods for.preparing steroids having thegroup I involve the reaction of osmium tetroxide with compoundscontaining the grouping II. This gives rise to substances having thegrouping III, which must then be oxidized onion onion -ornon (III) (IV)onion onion o--oN =0 Osmium tetroxide is an expensive reagent,and',"after:use the osmium must be recovered and reconvertediintothetetroxide if anything approaching economy is to: be

achieved. Moreover, the groupings II and are:themselves obtainable onlyby tedious prQcessesm'IOne of the commonly used methods, for example;for obtaining the grouping II is represented by the'transformationinvolving the skeleton Formulae VI, VII,"VIII, IXzarId II.

2,820,030 "-Pate Jen-01,4 109,58

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The l p y'of stepsv a clt etedigus. ca einy lxesl in "difiicultreactionsmake itgreatly clesirable to obtain a p r P s r "obta i ,compoun sshea zat c pi If Thus, rexamp e, a gemian iti s at liq ammonia and explosive.potassium are,involved in the transformation from VI to ,YII, Alsogreatest care. must tbe exercisedv in the partialcatalytichydrogenation, of

VII to'VIII.

Still a, further disadvantage f -the procedures outlin d "above residesin the necessitous preparation, as alk material, of compounds containingeitherthe system X or XI, both of which are jdifficult toobtain exceptin yery meageryields.

a-j-ixi 0 Recently great attentio'nthas beendirected to 3-keto- Acompounds containing inIaddition the grouping 1, be-

1 -cause of thediscovery that Kendalls compound E ofv the I Formula Ia:representstthe' firstltherapeutic agentfound :that definitelygalleviates .the pains= andaccompanying symptoms of rheumatoid arthritis;It therefore becoines of universal interest to seek intermediates whichmay simplify the preparation of Compound Enand :relatedssubstances,spare precious raw material and make them available at reduced costs.

I "CHaOH Kendalls compound E It is therefore an object of-the- -presentinvention to provide intermediates, useful for preparing substancesbearing the grouping I aud termed l7a-hydroxy-corticosteroids. 7

Other objects ,Will be apparent from the following description.

It has been found that the l7a-hydroxy steroids of the utype of KendallscompoundE and Reichsteinsrtcompound .Sqmay be obtained from readilyavailable 17-acetyl rStBIOidS. The starting materialslfor this type ofsynthesis are compounds containing,the grouping XII; namely, 17-acetyl-16,17-dehydrosteroids'. 5 The compounds containing the groupingXII are readily converted into the corre sponding 16,17oc-0Xid0compounds containing the grouping,=XIII by treatment with per benzoicacid. Where the initial starting materials are 5,l6-ppegnadienes such asmay be obtained by degradation of the side chain of diosgenin, and it isdesirable to retain the -6 double bond in the 16,17-oxido compound, theprocedure described in Patent No. 2,686,181, dated August 10, 1954, maybe employed. In the case of 16-pregnenes, however, such as may beobtained from sarsasapogenin, simple treatment ofthe pregnene withperbenzoic acid in a manner well known in the art is sufiicient.

We have now found that oxido compounds containing the grouping XIII, ontreatment with hydrobromic acid, sufie'r rupture of the oxido ring toproduce 16-bromo-17ahydroxy compounds containing the grouping XIV. Ontreatment of structure XIV with bromine in an appropriate solvent,compounds containing the structure XV result. 0n treatment of XV with ametallic salt of a carboxylic acid, such as potassium or sodium acetate,formate, benzoate, etc. in acetone, acetic acid or other suitablesolvent,

- the 2l-bromo group is replaced by an acyloxy group and the oi idostructure is regenerated, resulting in compounds containing thestructure XVI.

The attainment of structure XVI is a most novel and v far-reachingdevelopment in the steroid field, for a relatively simple andinexpensive procedure has herewith been developed for introduction ofthe ketol side chain and the 17a-hydroxy group into steroids. Thus,treatment of compounds containing the grouping XVI; namely, that of a2l-acyloxy-16,17u-oxido structure, with lithium aluminum hydride, suchas is described in Patent No. 2,662,904, dated December 15, 1953, leadssmoothly to 17a,20,2l-trihydroxy steroids (XVII), which compounds are ofextremetherapeutic significance. Moreover, protection of the 20-ketogroup by cyclic ethylene ketal formation, such as has been described inPatent No. 2,686,181, followed by reduction with lithium aluminumhydride and acid hydrolysis, leads to compounds .containing thestructure XVIII. Another method of introducing this structure is totreat the compounds possessing (IJH; CH CH3 CHgBr C=O {i=0 t=0 i=0 ---0H--0H I HBr I' Br, I- p t tXIV) omen CIEhOAcyl i i ----0H LtAlH with :Jintcrmzzdlate Y ketal formation (XVIII) (XVI) Standard 313/ \L.iAlHRaney N lcke Hydrolysis 011,0A 1 CHgOH I =0 HI OH 'Indlcatea eplmers.

Thus, a novel and economical method has been achieved for thepreparation of l7a-hydroxy steroids containing the 20,2l-ketol sidechain. Likewise, a novel and relatively inexpensive method has beenachieved for obtaining compounds containing the 17u-hydroxy group aswell as hydroxyl groups at positions 20,21.

In a specific illustration of this procedure, such as would be achievedin starting with 5,l6-pregnadiene-3fl ol-20-one acetate of the FormulaXX, the bromo compound corresponding to XV above would have thestructure represented by XXI. Naturally, such a compound, beforetreatment with potassium acetate in acetone to produce compoundscontaining the structure corresponding to XVI, must be dehalogenated atpositions 5 and 6 of the steroid nucleus. This is accomplished bytreatment with sodium iodide and leaves compounds of the structurerepresented by XXII, see'Patent No. 2,667,498, dated $H OHaBr (XX) (XXI)January 26, 1954. The'treatment of XXII with potassium acetate inacetone can now be carried out smoothly to give in excellent yield thel6,17-oxido-5-pregnene-3,2l-diol- 20-one,3,2l-diacetate, XXIII CHzICHIOAG 3 0 C=0 --0H Br 3 l .A :O-C A00 (XXII) (XXIII) The followingexamples will serve to illustrate the invention.

EXAMPLE 1 The preparation of a tetrabromide from 16,17-0xid0-5-pregnene-3fi-ol-20-one acetate A solution of one gram of16,l7a-oxido-pregnenolone acetate in 10 ml. of acetic acid was treatedwith a solution of 0.430 g. of bromine in 4.30 ml. of acetic acid atroom temperature. After the bromine color had all disappeared, 1.5 ml.of 30% HBr in acetic acid and 10 ml. of carbon tetrachloride was added,and the mixture was allowed to stand at room temperature for one-halfhour. An additional 0.430 g. of bromine in 4.30 ml. of acetic acid wasthen added. After standing for 1% hours at room temperature, the brominecolor had disappeared. The carbon tetrachloride was removed in vacuo andthe remaining acetic acid solution was poured into water. Thecrystalline precipitate was filtered, washed well with water and airdried. 1.79 g., M. P. -147 dec.

EXAMPLE 2 Preparation of 16,1 7-0xido-5-pregnene-35,21 dial-20- onediacetate The tetrabromide from Example 1 was dissolved in 25 ml. ofbenzene and a solution of 4.0 g. of sodium iodide in 25 ml. of ethanolwas added. This mixture was allowed to stand at room temperature for 20hours, and then poured into a large volume of ether and water. The etherlayer Q water.

with water and extracted with ether. was washed with water toneutrality, dried and concenaj-showed was washed with dilute sodiumthio'sulf ateand "water,

dried and concentrated in'vacuo' to a tan solid residue.

JThe total crude product was dissolved in 30 ml; of acetone, and 3.00 g.of freshly fused potassium acetate was added. The mixture was refluxedfor three hours, the acetone was removed by distillation and the residuewas diluted with water and extracted with ether.

EXAMPLE 3 Preparation of 21-benzoxy-16J 7 -oxid-5-pregnene- 33-0l-20-one acetate v, A solution of 2.14 g. of the tetrabromide of16,170:-

oxido-pregnenolone, prepared as in Example 1, in 30 ml.

of benzene was treated with a solution of 4.00 g. of

sodium iodide in 30 cc. of ethanol. The reaction mixture was allowed tostand at room temperature for20 hours and then poured into a largevolume of ether and The ether layer was washed with sodium thiosulfateand water, dried, and concentrated in vacuo to a tan solid. The totalcrude product was dissolvedin 30 ml. of acetone, and 3.0 g. of potassiumbenzoate was added. The mixture was refluxed for 3 hours, the acetonewas removed by distillation and the residue was diluted The ether layerhated to dryness. The solid residue was crystallized fromchloroform-methanol. 710 mg, M. P. 189-190, softens 180. Analysis.Calc.for C H O 0:73.14, H=7.36.

Found: C=72.94, H=7.57.

EXAMPLE 4 'The bromination of 16,17-oxido-5-pregnene-3fl-0l-20-0ne inacetic acid A solution of one gram of 16,lhuoxido-pregnenolone in ml. ofacetic acid was treated with 0.485 g. of bromine in 4.85 ml. of aceticacid at room temperature. After the bromine color had alldisappeared,'l.5 ml. of

30% HBr in acetic acid and ml. of carbon tetrachlov water and air dried.2.14 g., M. P. 145147 dec. There was no depression in melting point onadmixture with v the product from Example 1; therefore, acetylation atposition 3 has taken place in acetic acid in the presence of HBr. Theproduct when treated as in Example 2 yield16,17-oxido-5-pregnene-3;8,2l-diol-ZO-one diacetate,

' or when treated as in Example 3, 2l-benzoxy-16,17-

oxido-5-pregnene-3fi-ol-20-one acetate is obtained.

EXAMPLE 5 Treatment of 16,17-0xid0-pregnane-3-0l-20-0ne acetate To asolution of 1 gram of l6,17-oxido-pregnane-3- ol--one acetate in 10 ml.of acetic acid is added 1.5 ml. of HBr in acetic acid and 15 ml. ofcarbon tetrachloride. After one-half hour at room temperature there isadded 0.430 g. of bromine in 4.30 ml. of acetic acid. The mixture isallowed to stand at room temperature until the bromine color disappears.The carbon tetrachloride is then removed in vacuo and the acetic acidsolution poured into water, the precipitate filtered, washed well withwater and dried. The crude dibromide is then taken up in acetone and 3.0g. of freshly fused potassium 6 acetate added and the mixture "refluxedfor three hours. The reaction mixture is then worked up as in Example 2.

U EXAMPLE 6 16,1z-oxidesre i;enz 3p,21ammo-onezz-aioneaeemre A solutionof 10.0 g. of 16,l7 oxido-5-pregnene=3fiol-20-one acetate in' 100 ml. ofacetic acidandlOO ml. of carbon tetrachloride, chilled to 18, wastreated with a solution of 4.3 g. of bromine in 30ml. of carbontetrachloride. Upon complete decolorization, ;there was added 15 ml. ofa 32% solution of hydrobromic acid in acetic acid. After the solutionhad stood for ten minutes at room temperature, a second molar equivalentof bromine, 4.3 g. in 30 ml. of carbon tetrachloride,'was

added portionwise at room temperature with'stirring during aforty-minute period. The reaction mixture was allowed to stand for anadditional fifteen minutes and then evaporated in vacuo with a minimumof heating to remove the carbon tetrachloride. The remaining suspensionwas poured into water, filtered'andthe separated solid washed'with waterand dried at 40. The solid, 17.9 g., was dissolved in 75 ml. of'be'nzenefand. 175 'ml. of methanol, and after the addition of 5.2 g.ofhydro'gen bromine in 15 ml. of rnethanoLthe solution was allowed tostand at room temperature for ten hours. The ethereal extract of thereaction mixture which had been diluted with waterwas washed with Water,dried, concentrated to20 ml. and diluted with 155ml. of'benzene;- Afterthe addition of a solution of 365 g; of sodium iodide in 175ml. ofabsolute ethanol, the mixture was allowed to stand at room temperaturefor twenty-two hours. It

. was then diluted well with water andextracte'd with ether.

The ether extract was washed with 3% sodium thiosulfate solution andthen with water. 'The cream-colored residue (14.5 g.) remaining afterremoval of ether in vacuo was dissolved in 300 m1. of acetone containing42 g. of freshly-fused potassium acetate; The mixture was refluxed forfour and one-half hours, .then concentrated to a small volume, dilutedwith water and extracted with ether. The water-washed and dried etherealsolution gave upon concentration to a small volume, 5.5 g. of16,17-oxido-5-pregnene-3/3,21-diol-20-one 21 monoacetate melting at 188.A reslurry of the monoacetate in ether yielded 5.0 g. of materialmelting at 188- Further recrystallization from acetone ave needlesmelting at 19 0192. a ]'-14.9 (817 mg. made" up to 2 ml. withchloroform,OLD+0.065, 1, l"'d'm.).

Analysis.Calc. for C H O C=71.11; H 830. Found: (3:70.86; H=8.33.

EXAMPLE 7 16,1 7-0xid0-4-pregnene-21-0l-3,20-di0rze z zcetate sulfuricacid, 1% sodium hydroxide'solut ion and then with water to neutrality.Addition of 'petroleumether, B. P. 35-60, to the dried and concentrated(60 m1.)

ethereal solution gave 9.0 g. of 16,17-oxido-4-pregnene-21-ol-3,20-dione acetate in clusters of needles'melting at 168-170".From the mother liquor there was secured an additional 1.5 g. ofmaterialmelting at'165-168. Several recrystallizations fromether-petroleum ether, B. P. 3560, gave prisms melting at 170 -172.

, u +166.8 (71mg. made up to 2 mtwuhehlerefarm,

7 .EXAMPLE 8 I7oi-hydroxy-II-desoxycorticosterone acetate A solution of20 ml. of 32% hydrobromic acid in acetic acid was added to a solution of20.0 g. of 16,17-- 'oxido-4-pregnene-21-ol-3,20-dione acetate in 100 ml.of

* Found: C=59.26; H=7.05.

A solution of 23.5 g. of the bromohydrin in 750 ml. of ethanol wasstirred and refluxed with 98 g. of Raney nickel 1 for fivehours, andthen filtered while hot through a bed of filter-aid. The pale yellowfiltrate was concentrated in vacuo to a slurry of needle-like crystalsand chilled. The white solid was filtered and washed with 100 ml. ofcold acetone. After drying at 65, there was obtained 12.5 g. of17a-hydroxy-1l-desoxycorticosterone acetate melting at 226-231".Recrystallization from acetone raised the melting point to 235-238(sinters 230). This material showed no depression in melting point whenadmixed with a sample of the acetate of17ahydroxy-ll-desoxycorticosterone isolated from a natural source. a+ll4 (11.2 mg. made up to 5 ml. with acetone, o ;+0.255, 1, 1 dm.).

Analysis.-Calc. for C H O (3:71.11; H=8.30. Found: C=70.94; H=8.28.

An additional small crop of crude material was recovered from theoriginal mother liquor. The mother liquor was diluted with water,extracted with ether and washed with 1% sodium hydroxide solution andwith water. The dried ethereal solution was concentrated to a gummyresidue, which upon recrystallization from acetone gave 880 mg. ofmaterial melting at 19S220.

EXAMPLE 9 17a-hydroxy-1 I desoxycorticosterone A solution of 500 mg. of17a-hydroxy-1l-desoxycorticosterone acetate in 75 ml. of methanolcontaining 500 mg. of potassium bicarbonate in 10 ml. of water wasallowed to stand at room temperature for twenty-four hours. It was thendiluted with saline solution and extracted with freshly distilled ether.The ether solution was washed with water to neutrality, dried andconcentrated to 10 ml. After chilling, the separated solid was filteredand washed with cold ether. There resulted 290 mg. of fine, glisteningplates melting at ZOO-208.

Recrystallization of this material from acetone raised the melting pointto 207-208.

Many variations can be carried out in this type of preparation, asshould be obvious to one experienced in the art. Thus, compounds of thetype XXIH can be converted into -cyclic ethylene ketals before lithiumaluminum hydride reduction. Hydrolysis after lithium hydride treatmentwill then lead to 17a,21-hydroxy-20- keto compounds. Where a16,17-oxido-pregnane is the starting material, it is, of course, notnecessary to treat with sodium iodide, since removal of bromine from a5,6-dibromide is not necessary, and the 16,17-oxido compound can betreated directly with HBr and bromine and the resulting dibromidetreated with potassium acetate in acetone or other solvent. Replacementof the 21-bromine atom of the saturated compound with iodine can, of

1 Reactions 0! Hydrogen, Adkins, Univ. of Wisconsin Press, Madison,Wisconsin (1937).

(all

course, be resorted to if desired, and the resulting 21 iodo compoundtreated with potassium salt.

Also it is not essential to start with acetylated 3-hydroxy compoundswhere such are used. In the case of unsaturated oxido compounds,however, bromirration in acetic acid is convenient for the bromination,and under these conditions acetylation occurs. Other esters such as theformate, benzoate, etc. can be employed as starting material it theacetate is undesirable, and if the OH group is to be retainedunesterified, the bromination can be carried out under non-acetylatingconditions. However, it is preferred to start with acylated 3-hydroxycompounds and then to restore the 3-OH group after introduction of the21-halo group and before formation of the 21-acyloxy group. This can bedone by subjecting the 3-acyloxy-21-halo compound to a mild hydrolysiswith HBr in methyl alcohol, as shown in Example 6. Where the compoundsalso contain a 5,6-di-- bromo grouping, the hydrolysis can take placeeither be-- fore or after removal of the 5,6-bromine atoms andreplacement of the 21-bromine atom with iodine. Likewise, other saltsthan the acetate and benzoate, such as the: propionate and the like, canbe employed for replacement of the 2l-halogen atom and for restorationof the 16,17- oxido group.

Also many other pregnanes and pregnanes can be used in the presentinvention. Thus, pregnenes and pregnanes possessing an oxygenatedfunction, such as keto, hydroxy and a-cyloxy groups, at the 11- or12-position of the nucleus can be treated to form the2l-hydroxy-l7-oxygenated derivatives. Starting compounds oxygenated inring C can, for example, be prepared from bile acids, such asdesoxycholic acid, by degradation of the side chain and formation of a Adouble bond, by known methods, such as that of Butenandt et al., Ber.71, 1487 (1938); 72, 182 (1939). Where an ll-oxygenated compound isdesired, the transposition can be carried out either after thedegradation of the side chain or after the reactions here described havebeen carried out.

It is thus seen that intermediates are provided which are useful forproducing 17a-hydroxy-21-hydroxy pregnenes and pregnanes from steroidswhich do not possess these groupings Without the use of expensive and/ordangerous reagents. Since the starting materials are much more readilyavailable than the natural substances containing such groupings, thisinvention assumes particular significance in view of the widespreadinterest in such hydroxylated steroids in the treatment of rheumatoidarthritis.

This application is a division of Serial No. 143,146, filed February 8,1950.

Having described the invention, what is claimed is:

1. A steroid selected from the class consisting of 16,17-oxido-S-pregnene-3,2l-diol-ZO-one, the acylates of 16,17-oxido-5-pregnene-3,21-diol-20-one in which the acyloxy group is theacyloxy group of a lower hydrocarbon carboxylic acid containing not morethan seven carbon atoms, 16,17-oxido-4-pregnene-21-ol-3,ZO-dione and theesters of l6,17-oxido-4-pregnene-21-ol-3,20-dione with lower hydrocarboncarboxylic acids containing not more than seven carbon atoms.

2. 16,17-oxido-5-pregnene-3,21-diol-20-one diacetate.

3. l6,l7-oxido-5pregnene-3,2l-diol-20-one 21-monoacetate.

4. 16,17-oxido-4-pregnene-21-ol-3,20-dione acetate.

5. The 3,2l-diesters of 3,2l-dihydroxy-l6,l7-oxido-20- keto-5-pregnenewith lower hydrocarbon carboxylic acids containing not more than sevencarbon atoms.

6. A 21-monoester of 3,21-dihydroxy-16,l7-oxido-20- keto-S-pregnene witha lower hydrocarbon carboxylic acid containing not more than sevencarbon atoms.

No references cited.

1. A STERIOD SELECTED FROM THE CLASS CONSISTING OF16,17OXIDO-5-PREGENE-3,21-DIOL-20-ONE, THE ACYLATES OF16,17OXIDO-5-PREGNENE-3,21-DIOL-20-ONE IN WHICH THE ACYLOXY GROUP IS THEACYLOXY GROUP OF A LOWER HYDROCARBON CARBOXYLIC ACID CONTAINING NOT MORETHAN SEVEN CARBON ATOMS, 16,17-OXIDO-4-PREGENE-21-OL-3,20-DIONE AND THEESTERS OF 16,17-OXIDO-4-PREGNENE-21-OL-3,20-DIONE WITH LOWER HYDROCARBONCARBOXYLIC ACIDS CONTAINING NOT MORE THAN SEVEN CARBON ATOMS.